Discovery of N-(5-Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238): A Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5 Selected for Clinical Evaluation.

Felts AS, Rodriguez AL, Blobaum AL, Morrison RD, Bates BS, Thompson Gray A, Rook JM, Tantawy MN, Byers FW, Chang S, Venable DF, Luscombe VB, Tamagnan GD, Niswender CM, Daniels JS, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
J Med Chem. 2017 60 (12): 5072-5085

PMID: 28530802 · PMCID: PMC5484149 · DOI:10.1021/acs.jmedchem.7b00410

Preclinical evidence in support of the potential utility of mGlu NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu versus the other mGlu receptors, and binding studies established a K value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.

MeSH Terms (16)

Allosteric Regulation Aminopyridines Animals Chemistry Techniques, Synthetic Drug Evaluation, Preclinical HEK293 Cells High-Throughput Screening Assays Humans Macaca fascicularis Male Mice, Inbred Strains Picolinic Acids Rats, Sprague-Dawley Receptor, Metabotropic Glutamate 5 Structure-Activity Relationship Tissue Distribution

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